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Cancer therapy using oligonucleotide-based STAT3 inhibitors: will they deliver?

    Marcin Kortylewski

    * Author for correspondence

    Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA.

    &
    Sergey Nechaev

    Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Published Online:https://doi.org/10.4155/tde.13.152
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    References

    • Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer2(10),740–749 (2002).
    • Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer9(11),798–809 (2009).
    • Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr. Opin. Pharmacol.12(4),464–470 (2012).
    • Sen M, Thomas SM, Kim S et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov.2(8),694–705 (2012).
    • Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov.11(2),125–140 (2012).
    • Burel SA, Han SR, Lee HS et al. Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther.23(3),213–227 (2013).
    • ClinicalTrials Database. www.clinicaltrials.gov
    • Zammarchi F, De Stanchina E, Bournazou E et al. Antitumorigenic potential of STAT3 alternative splicing modulation. Proc. Natl Acad. Sci. USA108(43),17779–17784 (2011).
    • Rettig GR, Behlke MA. Progress toward in vivo use of siRNAs-II. Mol. Ther.20(3),483–512 (2012).
    • 10  Peschansky VJ, Liang Z, Wahlestedt C. RNAi joins the ‘singles club’. Mol. Ther.20(11),2010–2011 (2012).
    • 11  Thiel KW, Giangrande Ph. Intracellular delivery of RNA-based therapeutics using aptamers. Ther. Deliv.1(6),849–861 (2010).
    • 12  Ma Y, Kowolik CM, Swiderski PM et al. Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA. ACS Chem. Biol.6(9),962–970 (2011).
    • 13  Zhou J, Bobbin ML, Burnett JC, Rossi JJ. Current progress of RNA aptamer-based therapeutics. Front. Genet.3,234 (2012).
    • 14  Latz E, Schoenemeyer A, Visintin A et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol.5(2),190–198 (2004).
    • 15  Nechaev S, Gao C, Moreira D et al. Intracellular processing of immunostimulatory CpG-siRNA: Toll-like receptor 9 facilitates siRNA dicing and endosomal escape. J. Control. Release170,307–315 (2013).
    • 16  Kortylewski M, Swiderski P, Herrmann A et al.In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat. Biotechnol.27(10),925–932 (2009).
    • 17  Zhang Q, Hossain DM, Nechaev S et al. TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. Blood121(8),1304–1315 (2013).
    • 18  Hossain DM, Dos Santos C, Zhang Q et al. Leukemia cell-targeted STAT3 silencing and TLR9-triggering generate systemic antitumor immunity. Blood123(1),15–25 (2013).
    • 19  Mcnamara JO 2nd, Andrechek ER, Wang Y et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat. Biotechnol.24(8),1005–1015 (2006).
    • 20  Zhou J, Tiemann K, Chomchan P et al. Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells. Nucleic Acids Res.41(7),4266–4283 (2013).
    • 21  Gao C, Kozlowska A, Nechaev S et al. TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy. Cancer Res.73(24),7211–7221 (2013).